Cystein, Intestinal Thiols and Goblet Cell Development

半胱氨酸、肠硫醇和杯状细胞发育

基本信息

  • 批准号:
    6762359
  • 负责人:
  • 金额:
    $ 25.81万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2003
  • 资助国家:
    美国
  • 起止时间:
    2003-07-01 至 2008-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The proposal originates from our observations of a three to four fold increase in the number of acidomucin-positive goblet cells accompanied by glutathione (GSH) depletion in the small intestinal mucosa of neonatal pigs being nourished parenterally. We hypothesize that the lack of luminal cysteine is the primary insult perceived by the parenterally nourished epithelium, and that the functional endpoint of this nutritional deficiency is a more oxidized intracellular redox potential The identification of this amino acid as a key nutritional factor is based on (a) the high rate of first-pass consumption of dietary cysteine and the low rate of arterial cysteine utilization by the intestine; (b) evidence that cellular redox status is a key determinant of cellular differentiation, and (c) the fact that cysteine is structurally and functionally involved in both intracellular redox status and mucosal defense via its inherent contribution to the thiol buffers GSH and thioredoxin (Trx) on one hand, and the goblet cell-specific secretory mucins and intestinal trefoil factor (ITF) on the other. We hypothesize that parenteral nutrition results in a preferential activation of the mucous cell lineage as well as selective sparing of goblet cells leading to the repopulation (at a reduced rate) of the villus with goblet cells relative to absorptive enterocytes. The alteration in goblet cell development is initiated by hyperoxia that stems from compromised cysteine status. In other words, we hypothesize that goblet cells are the guardians of mucosal redox homeostasis. Our hypothesis will be tested in three specific aims: 1) Determine if a causal relationship exists between epithelial redox status and goblet cell expansion, independent of TPN-associated inflammation. 2) Quantify, in a goblet cell culture model system, the hierarchy of cysteine usage for the synthesis of GSH and Trx versus ITF and secretory mucins, as well as the role of the transsulfuration pathway in the formation of cysteine and sulfate from methionine, as affected by apical versus basal provision of cysteine, and in response to graded levels of hyperoxia. Simultaneously, determine if the source (inorganic vs. cysteine-derived) and flux of sulfate used for sulfomucin biosynthesis is affected by cysteine availability and hyperoxic stress. 3) Test the hypothesis that Cysl31 and/or Cys165, found within the activation domain of Cdx2, are redox sensitive and upon post-translational modification alter the specificity of Cdx2 transcriptional regulation.
描述(申请人提供):该建议源于我们观察到,在接受肠外营养的新生猪的小肠粘膜中,酸性粘蛋白阳性的杯状细胞数量增加了三到四倍,并伴随着谷胱甘肽(GSH)的耗竭。我们假设缺乏腔内半胱氨酸是肠外营养上皮感觉到的主要损害,而这种营养缺乏的功能终点是细胞内氧化还原电位。这种氨基酸是基于(A)饮食半胱氨酸的高首过消耗率和肠对动脉半胱氨酸的低利用率而被确定为关键营养因素的;(B)证据表明细胞的氧化还原状态是细胞分化的关键决定因素,以及(C)半胱氨酸通过其对硫醇缓冲液GSH和硫氧还蛋白(TRX)以及杯状细胞特异性分泌粘蛋白和肠道三叶因子(ITF)的固有贡献,在结构和功能上参与细胞内的氧化还原状态和粘膜防御。我们假设肠外营养导致粘液细胞系的优先激活以及杯状细胞的选择性保留,从而导致绒毛中杯状细胞相对于吸收性肠细胞的再繁殖(以降低的速度)。杯状细胞发育的改变是由半胱氨酸状态受损引起的高氧引起的。换句话说,我们假设杯状细胞是粘膜氧化还原动态平衡的守护者。我们的假设将在三个具体目标中得到验证:1)确定上皮氧化还原状态和杯状细胞扩张之间是否存在因果关系,独立于TPN相关的炎症。2)在杯状细胞培养模型系统中,量化半胱氨酸用于合成GSH和TRX与ITF和分泌性粘蛋白的等级,以及半胱氨酸转化途径在蛋氨酸合成半胱氨酸和硫酸盐中的作用,半胱氨酸的顶端供应与基础供应的影响,以及对分级高氧水平的响应。同时,确定用于硫粘蛋白生物合成的硫酸盐的来源(无机和半胱氨酸来源)和通量是否受到半胱氨酸可获得性和高氧胁迫的影响。3)验证这样的假设,即在CDX2的激活域中发现的Cysl31和/或Cys165是氧化还原敏感的,并且在翻译后修饰时改变了CDX2转录调控的特异性。

项目成果

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Rex Gaskins其他文献

Rex Gaskins的其他文献

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{{ truncateString('Rex Gaskins', 18)}}的其他基金

Diet modulation of bacterial sulfur & bile acid metabolism and colon cancer risk
细菌硫的饮食调节
  • 批准号:
    9751249
  • 财政年份:
    2016
  • 资助金额:
    $ 25.81万
  • 项目类别:
Diet modulation of bacterial sulfur & bile acid metabolism and colon cancer risk
细菌硫的饮食调节
  • 批准号:
    9094223
  • 财政年份:
    2016
  • 资助金额:
    $ 25.81万
  • 项目类别:
FRET-based Biosensors to Monitor Redox in Cell Cycle Regulation
基于 FRET 的生物传感器可监测细胞周期调节中的氧化还原
  • 批准号:
    8305728
  • 财政年份:
    2010
  • 资助金额:
    $ 25.81万
  • 项目类别:
FRET-based Biosensors to Monitor Redox in Cell Cycle Regulation
基于 FRET 的生物传感器可监测细胞周期调节中的氧化还原
  • 批准号:
    7946135
  • 财政年份:
    2010
  • 资助金额:
    $ 25.81万
  • 项目类别:
FRET-based Biosensors to Monitor Redox in Cell Cycle Regulation
基于 FRET 的生物传感器可监测细胞周期调节中的氧化还原
  • 批准号:
    8129427
  • 财政年份:
    2010
  • 资助金额:
    $ 25.81万
  • 项目类别:
Cystein, Intestinal Thiols and Goblet Cell Development
半胱氨酸、肠硫醇和杯状细胞发育
  • 批准号:
    6911639
  • 财政年份:
    2003
  • 资助金额:
    $ 25.81万
  • 项目类别:
Cystein, Intestinal Thiols and Goblet Cell Development
半胱氨酸、肠硫醇和杯状细胞发育
  • 批准号:
    6678652
  • 财政年份:
    2003
  • 资助金额:
    $ 25.81万
  • 项目类别:
Cystein, Intestinal Thiols and Goblet Cell Development
半胱氨酸、肠硫醇和杯状细胞发育
  • 批准号:
    7087054
  • 财政年份:
    2003
  • 资助金额:
    $ 25.81万
  • 项目类别:
Cystein, Intestinal Thiols and Goblet Cell Development
半胱氨酸、肠硫醇和杯状细胞发育
  • 批准号:
    7261250
  • 财政年份:
    2003
  • 资助金额:
    $ 25.81万
  • 项目类别:
ENVIRONMENTAL MODULATION OF INTESTINAL SULFIDOGENS AND I
肠道硫化物和 I 的环境调节
  • 批准号:
    6178806
  • 财政年份:
    1999
  • 资助金额:
    $ 25.81万
  • 项目类别:

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